Signals arising from the gastrointestinal tract in response to the presence of nutrients are important to the control of food intake. During ingestion, multiple gastrointestinal sites are stimulated by nutrient digestion products and this stimulation initiates local gastrointestinal actions and produces both neural and peptide signals that provide feedback information on the nature and amount of gastrointestinal contents. The ability of individual gut peptides to affect food intake has been well demonstrated. The experiments in the current proposal take a translational approach to examine the ability of combinations of gut peptide agonist compounds to have beneficial effects on weight loss. A number of pharmacological approaches for obesity treatment are currently available but their efficacy is limited and does not approach that of bariatric surgery to produce significant and sustained reduction in excess weight. The proposed experiments will examine multiple actions of peptide agonist combinations in both rodent and nonhuman primate models. In Aim 1, we will identify the degree to which paired dose combinations of CCK, GLP-1 and amylin agonists can have additive or synergistic effects on gastric emptying, food intake and body weight. We will examine short-term interactions using lean rats and rhesus monkeys and the effects of chronic dose combinations on body weight using DIO rats and our novel Bonnet macaque obesity model. Additional experiments will focus on the ability of dose combinations to maintain weight loss produced by caloric restriction in DIO rats. In Aim 2, we will begin to examine potential mechanisms underlying the ability of gut peptide dose combinations to reduce food intake and body by assessing the effects of agonist combinations on measures of palatability and reward by examining brief access licking and progressive ratio responding. In Aim 3, we will identify neural sites of interaction for dose combinations and their effects on gene expression and neuronal signaling pathways. We will use c-fos as a marker of neural activation to identify brain sites demonstrating synergistic interactions. We will examine changes in mRNA expression for peptides, neurotransmitters and receptors further investigate mechanisms underlying the synergistic interactions of the agonists on food intake and body weight by examining how dose combination modulate activity in signaling pathways that have been demonstrated to play roles in the feeding inhibitory actions of the peptide agonists. Together these experiments will test the overall hypothesis that combinations of gut peptide agonist compounds can provide an important approach in the current obesity epidemic. Bariatric surgery is the only current successful long-term weight loss strategy for severe obesity. Bariatric surgery results in significant alterations in gut peptide secretion and mimicking aspects of this with combinations of long acting gut peptide agonists may provide a less invasive approach to promote weight loss.